Depression is a serious complication of structural brain injury, and can severely impair physical and cognitive recovery. Of the three million stroke survivors living in the US, more than 65 percent of them will suffer clinical symptoms of depression. Many of these cases can be directly attributable to the stroke, making post-stroke depression a serious health problem. The specific aim of this proposal is to study the biological bases of depression as revealed through patients recovering from ischemic focal brain injury. These studies of depression will focus on its effects on motor system plasticity after middle cerebral artery infarction. We will test the following hypotheses: Motor cortices in clinically depressed subjects will present neurochemical changes in monoaminergic systems (Serotonin, dopamine and noradrenaline). Recovery of motor skills after frontal ischemic stroke depends on the anatomical reorganization of ipsilateral frontal regions adjacent to the infarcted area, and these anatomical changes will be more pronounced in individuals without depression when compared to cases with post-stroke depression. Functional neuroimaging will corroborate the anatomical findings, demonstrating poorer anatomical recovery in depressed patients than in those without depression. Areas underlying functional recovery as seen with fMRI will show the greatest degree of anatomical reorganization when assessed with direct anatomical methods in non-depressed cases compared to depressed ones. The overriding goal of this research is to investigate the neuroanatomical and neuropharmacological differences between depressed and non-depressed patients following focal ishemic brain damage, and to correlate the findings from studies of autopsy tissue with neuroimaging studies using functional magnetic resonance imaging (fMRI). Since combining both methods will limit the number of cases, in parallel, we will perform the same neuroantomical studies in post-mortem tissue with damage in the equivalent areas (but without fMRI assessment). The detection of the changes in cellular circuitry during recovery in groups with and without post-stroke depression will allow us to understand better the neurobiological substrate of this disorder. In the long run, this information may lead to novel pharmacological treatments in both depression and stroke, but most importantly, in those cases where depression is a concomitant of structural brain injury. At the same time, the current research aims to give the principal investigator necessary mentored experience to achieve independence in biological psychiatry research.